This Program Grant presents both a technically and conceptually intertwined series of experiments to understand the biology of cell signaling and tot elucidate the molecular events by which perturbations in signaling pathways lead to the conversion of a normal cell to a tumor cell. New technology in molecular biology and genetics, gene targeting, and transgenesis now permit an analysis of the function of these genetic elements at an organismic level. In this proposal we ask: "What is the nature of the extracellular signaling molecules? How does the association of these molecules with cell surface receptors transmit a structural change most often reflected by receptor oligomerization past the hydrophobic membrane? How are changes in the intracellular domain of the receptor recognized by downstream signaling components to alter the growth and differentiation of individual cells in cell populations? Finally, how do perturbations in this process result in the malignant phenotype? Specific experiments address the role of retinoic acid as a signaling molecule, the function of the transmembrane receptors, RET and Eph kinases, and the biology of the cytoplasmic kinases, abl. Thus, the molecular dissection of receptor-mediated cell signaling during development and cell transformation continues to be the principal goal of the long standing Program Project.